Pegylated (PEG, polyethylene glycol) reagents have been commercialized in order to enhance the desirable properties of protein drugs, peptides, oligonucleotides, antibodies and small molecules. Polyethylene glycol is inert, non toxic and has been approved by the FDA for human administration. There are several pegylated protein drugs on the market including PEG interferon as a treatment for hepatitis, and PEG asparaginase as a treatment for cancer. There are two main types of commercially available PEG reagents, Linear and Branched. In preparing the branched polyethylene glycols from lysine, the resulting lysine derivatives are racemic and the branches have identical peg polymer molecular weights.
The present invention is a novel branched methoxy pegylated lysine derivative in that it is enantiomerically pure, and affords the option for the formation of branched lysine PEGs that have either the same or different molecular weights on each branch. The described enantiomerically pure mPEG derivative has not been reported in the literature, and therefore represents a new chemical entity (NCE). It is prepared from known and commercially available materials, and therefore amenable to commercial manufacturing. Pegylated drugs generally improve the pharmacokinetics and pharmacodynamics of pharmaceuticals. There are many reported advantages of pegylated drugs over non-pegylated drugs, the most important of which are the potential for increased efficacy and lower toxicity. Among the other reported advantages of pegylated drugs over non pegylated drugs are an increase in bioavailability, lower dose levels, increased half life, improved stability, enhanced solubility, sustained absorption, reduced dosing frequency, reduced renal clearance, reduced immunogenicity, reduced antigenicity, reduced proteolysis, and potential for site directed mutagenesis.
As pegylation technology matures and process development improves, the potential to significantly reduce the cost of drugs through reduced dosing requirements will be realized. The potential synergistic effect of drugs can be enhanced through multiple drugs being bound to branched mPEGs. Current drugs not tolerated by patients now have the potential to be tolerated since the dose requirements will be significantly reduced. Through manipulation of the specific drug with a specific molecular weight mPEG, optimization of efficacy can be achieved. The combination of lower dose, less frequent administration, lower toxicity, less side effects, and increased tolerability will improve quality of life for patients. Overall, the potential of pegylated drugs is difficult to overestimate. Through multiple oligopeptide molecules, the potential for a host of new molecular entities (NCEs) exists. Since the safety and efficacy of existing drugs has already been established, pegylation of those drugs which are currently not tolerated for various reasons, have the potential to enhance the desirable pharmacological properties and should result in rapid approvals by the FDA and other regulatory agencies. Due to the resulting low dose levels of pegylated drugs, drugs difficult to obtain will now be more readily available since the amounts for each patient will have been significantly reduced. New chemical entities will have a higher probability of approval due to the lower toxicity and higher efficacy than if they remained non-pegylated. Older drugs previously rejected for toxicity and efficacy reasons now have the potential to be viable drugs and should be reexamined as pegylated derivatives.
This invention has the potential to significantly increase the number of drugs currently available. The mPEG polymerization of drugs will enhance the intellectual property protection afforded through new chemical entity status.